Zomiradomide

CAS 2655656-99-6

MF C45H48F3N7O6S MW871.97

• N-[2-[4-[[6-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethyl]-2-azaspiro[3.3]heptan-2-yl]methyl]cyclohexyl]-5-(2-hydroxypropan-2-yl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide
• N-[2-[trans-4-[[6-[2-[[2-(2,6-Dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]ethyl]-2-azaspiro[3.3]hept-2-yl]methyl]cyclohexyl]-5-(1-hydroxy-1-methylethyl)-6-benzothiazolyl]-6-(trifluoromethyl)-2-pyridinecarboxamide

antineoplastic, IRAK degrader-1, AQ5UXV5646

Zomiradomide is an orally active PROTAC degrader for IRAK4 (DC₅₀=6 nM), thereby inhibiting the NF-κB signaling pathway. Zomiradomide acts also as a molecular glue, recruiting Ikaros and Aiolos, and mediating their degradation (DC₅₀ for Ikaros is 1 nM), thereby activating the type I IFN signaling pathway.

Zomiradomide is a small molecule protein degrader of interleukin-1 receptor-associated kinase 4 (IRAK4) and the immunomodulatory imide drug (IMiD) substrates Ikaros (IKZF1) and Aiolos (IKZF3), with potential immunomodulating and antineoplastic activities. Upon administration, zomiradomide modulates the E3 (ubiquitin) ligase and targets IRAK4, Ikaros and Aiolos for ubiquitination. This induces proteasome-mediated degradation of IRAK4, Ikaros and Aiolos. The degradation of IRAK4 inhibits IRAK4-mediated signaling and prevents the activation of IRAK4-mediated nuclear factor-kappa B (NF-kB) signaling and decreases the expression of inflammatory cytokines and certain pro-survival factors. This inhibits the proliferation of IRAK4-overactivated tumor cells, which are found in cells harboring MYD88 activating mutations or those with overactivated toll-like receptor (TLR) pathways. The degradation of the transcription factors Ikaros and Aiolos leads to a downregulation of other proteins, including interferon regulatory factor 4 (IRF4), which upregulates type I interferon signaling and further inhibits NF-kB activation. This leads to apoptosis and the inhibition of tumor cell proliferation. IRAK4, a serine/threonine-protein kinase that plays a key role in both the TLR and IL-1R signaling pathways, is activated though the adaptor protein MYD88 and links the TLR and IL-1R signaling pathway to the NF-kB pathway.

SYN

WO2022027058

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022027058&_cid=P20-MJGJKA-81687-1

Example 1. Synthesis of N-[2-[4-[[6-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethyl]-2- azaspiro[3.3]heptan-2-yl]methyl]cyclohexyl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Compound A)

[00349] To a solution of 4-[2-(2-azaspiro[3.3]heptan-6-yl)ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline -1,3-dione (75.8 mg, 148 umol, TFA salt, Intermediate ATH) in THF (2 mL) was added TEA (15.0 mg, 148 umol), then the mixture stirred at 25 °C for 10 min. Next, HOAc (8.92 mg, 148 umol) and N-[2-(4-formylcyclohexyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (73.0 mg, 148 umol, Intermediate BAX) were added to the mixture and the mixture was stirred at 25 °C for 20 minutes, then NaBH(OAc)₃ (62.9 mg, 297 umol) was added to the mixture at 0 °C. The reaction mixture was stirred at 0-25 °C for 2 hours. On completion, the reaction mixture was quenched with H2O (1 mL) and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water(0.225%FA)-ACN]; B%: 31%-58%, 9 min) to give the title compound (59.1 mg, 41% yield) as a yellow solid.¹H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 11.09 (s, 1H), 9.06 (s, 1H), 8.49 – 8.44 (m, 1H), 8.38 (t, J = 8.0 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.10 – 6.99 (m, 2H), 6.47 (t, J = 5.6 Hz, 1H), 6.07 (s, 1H), 5.05 (dd, J = 5.6, 12.8 Hz, 1H), 3.54 – 3.47 (m, 2H), 3.25 – 3.18 (m, 4H), 3.06 – 2.99 (m, 1H), 2.93 – 2.83 (m, 1H), 2.63 – 2.56 (m, 1H), 2.54 (s, 3H), 2.30 – 2.21 (m, 2H), 2.30 – 2.21 (m, 3H), 2.06 – 1.99 (m, 1H), 1.88 – 1.77 (m, 4H), 1.68 – 1.61 (m, 8H), 1.58 – 1.49 (m, 2H), 1.45 – 1.36 (m, 1H), 1.15 – 1.02 (m, 2H); LC-MS (ESI+) m/z 872.2 (M+H)⁺.

PAT

• Irak degraders and uses thereofPublication Number: US-2024131016-A1Priority Date: 2019-12-17
• Irak degraders and uses thereofPublication Number: EP-4076520-A1Priority Date: 2019-12-17
• IRAK degraders and uses thereofPublication Number: US-11779578-B2Priority Date: 2019-12-17Grant Date: 2023-10-10
• IRAK degraders and uses thereofPublication Number: US-11707457-B2Priority Date: 2019-12-17Grant Date: 2023-07-25
• Methods of treating mutant lymphomasPublication Number: US-2024316004-A1Priority Date: 2020-07-30
• Methods of treating mutant lymphomasPublication Number: US-2022054453-A1Priority Date: 2020-07-30
• Irak degraders and uses thereofPublication Number: US-2023144292-A1Priority Date: 2019-12-17
• Irak degraders and uses thereofPublication Number: WO-2021127190-A1Priority Date: 2019-12-17
• Irak degraders and uses thereofPublication Number: US-2021228562-A1Priority Date: 2019-12-17
• Irak4 degraders and uses thereofPublication Number: EP-4463166-A1Priority Date: 2022-01-14
• Methods of treating mutant lymphomasPublication Number: WO-2022027058-A1Priority Date: 2020-07-30
• Methods of treating mutated lymphomaPublication Number: CN-116133692-APriority Date: 2020-07-30
• Methods of treating mutant lymphomasPublication Number: US-11857535-B2Priority Date: 2020-07-30Grant Date: 2024-01-02
• Methods of treating mutant lymphomasPublication Number: EP-4188374-A1Priority Date: 2020-07-30
• Irak4 degraders and uses thereofPublication Number: WO-2024191788-A1Priority Date: 2023-03-10
• Formulations for treating cancerPublication Number: WO-2024163751-A1Priority Date: 2023-02-01
• Irak4 degraders and uses thereofPublication Number: WO-2024148049-A1Priority Date: 2023-01-04
• Irak4 degraders and uses thereofPublication Number: US-2023277519-A1Priority Date: 2022-01-14
• Irak4 degraders and uses thereofPublication Number: WO-2023137439-A1Priority Date: 2022-01-14

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[1]. Weiss Matthew M. Preparation of benzothiazole derivatives as IRAK degraders and uses thereof. World Intellectual Property Organization, WO2021127190 A1. 2021-06-24.[2]. Zeng S, et al. Current advances and development strategies of orally bioavailable PROTACs. Eur J Med Chem. 2023 Dec 5;261:115793.  [Content Brief][3]. Weiss MM, et al., Discovery of KT-413, a Targeted Protein Degrader of IRAK4 and IMiD Substrates Targeting MYD88 Mutant Diffuse Large B-Cell Lymphoma. J Med Chem. 2024 Jul 11;67(13):10548-10566.  [Content Brief]

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